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Machado AC, Sugaya NN, Migliari DA, Matthews RW.

Machado AC, Sugaya NN, Migliari DA, Matthews RW.

Chattopadhyay A.

Colella G, Itro A, Corvo G.

Chaudhary S.

Soto Araya M, Rojas Alcayaga G, Esguep A.

 Romero MA, Seoane J, Varela-Centelles P, Diz-Dios P, Garcia-Pola MJ.

Koray M, Dulger O, Ak G, Horasanli S, Ucok A, Tanyeri H, Badur S.

Eisen D.

Denli YG, Durdu M, Karakas M.

Chung CH, Yang YH, Chang TT, Shieh DB, Liu SY, Shieh TY.

Brazilian academic structure  

Grinspan’s syndrome

Abstract                            Results (tables)>>>>  

A rare case of ulcerative lichen planus manifesting itself in patient diabetic and with hypertension (Grinspan's syndrome), who developed benign (micro follicular thyroid adenoma) and malign neoplasm (skin epidermoid carcinoma) was reported, discussing the manifestation of lichen planus and its possible association with the variables such as glucose level, diastolic and systolic pressures, and emotional and/or physical stress. For this, the results of control glucose level realized at three different laboratories, and realized in abrosia of 12 hours, in the period from 1995 to 2002, were submitted to Student's parametric test at (p<0.01) 99 or (p<0.05) 95% significance level, whose results presented significant statistic difference between 1995 (first manifestation of lichen planus and high glycemia) and 1997 (absence of lichen planus and controlled glycemia). The glucose level presented low statistic correlation with the manifestation of lichen planus (0.082), and high correlation with the emotional/or physical stress (0.601), while this latter presented a low positive correlation (0.447) with the manifestation of lichen planus. Under emotional and/or physical stress (orthopedic surgery) was verified significant statistic difference (Student's test) in the glucose level (p=0.011), systolic (p=0.035) and diastolic (p=0.035) pressures between the period next to surgery (January+April) and post-surgical (May + Jun). During this period, a low correlation was verified between glucose level and systolic (0,097) and diastolic (0.066) pressure. However, a high positive correlation was identified between glucose level and systolic (0.996) and diastolic (0.692) pressure in the period pre-surgical (January), while in the period post-surgical of 45 days (April) occurred a high positive correlation between glucose level and systolic (0.631) pressure, but a low correlation between the glucose level and diastolic (0.157) pressure, indicating a possible association between stress, glucose level and blood pressure. These results indicated that the emotional and/or physical stress is associated with the elevation of the glucose level and systolic and diastolic pressures, as well as to lichen planus manifestation. However, other factors may also be involved. Therefore, these data suggest - in the diabetic patient fur us studied - there be an association among the glucose level, blood pressure and manifestation of oral and dermal lichen planus lesions, particularly, in its first manifestation and recurrence of dermal and oral lesions; as well as suggest that the lichen planus presents a malignance potential, considering that the patient developed dermal carcinoma after the first manifestation of lichen planus.  

Thyroid Adenoma (photoscan and echography), goiter, nodule and calcification

Introduction                                     Next case >>>> 

Lichen planus lesion was described by the first time by Erasmus Wilson, in 1869, as a skin disease that may also be classified so inflammatory as autoimmune disease, which also to manifest itself in the oral mucosa. Not infrequently the oral lesions appear before of the skin lesions, and in certain cases may be diagnosed without the realization of biopsy. Occur between 0.5 and 1.9% of the population, in all the races and in both the sexes. However, is more frequently identified in females; presenting the ratio female to males of 2:1.The majority of the cases are diagnosed between 30 and 60-years-old. Around from 10 to 45% of the patients with oral lesions also present skin lesions, which may be identified conjunctly, or afterward the remission of the oral lesions. Clinically may present itself with the aspects reticular, papular, atrophic, bullous, or erosive. Of these, the reticular aspect has been reported as the most frequently observed. The expert observation of these lesions shows the presence of Wickhan's strias (thin and elevate white lines), whose differential diagnosis must always be made with the leukoplakia, pemphigus, pemphigoid, multiform eritema, syphilis, recurrent aphta and lupus erythematous. Malign transformation Although 20% of the lesions suffer spontaneous remission, around of 1.2% cases may suffer malign transformation, of what the erosive aspect presents the greatest potential. Recent studies about the malignant potential of the oral lichen planus provided clinical evidence that patients affected for lichen planus have a rise in the risk of developing oral squamous cell carcinoma, since in a group of 502 patients with oral lichen planus, in 5 years of study, 24 (20.9%) patients developed carcinomas. Of these, 28.5% were carcinoma in situ, 38% micro-invasive carcinomas, 28.5% stage I, and 4.7% stage II carcinomas (Mignogna et. al., 2001). This potential, at least in part, may be explicated by genetic instability in the chromosome 9 - monosomy and overexpression of p53 protein (Valente G et al., 2001; Kin et al. 2001), which has been connected to dysplakia and lost of differentiation - in pre-malignant and malign lesions - as well as to the increase of the cellular proliferation rate identified for the rise of PCNA expression (Girod, Pape, Kruerger, 1995; Martinez-Lara et al., 1996). Was also suggested the possibility of alterations in the expression of 55 and 75-kDa TNF receptors and alterations in the synthesis of this growth factor to be connected to evolution to squamous cell carcinoma, since this cytokine was identified throughout of the epithelium of lichen planus, leukoplakia and squamous cell carcinoma, while occasional cells TNF-positives were identified in the normal epidermis and oral mucosa (Younes et al., 1996). Malignant transformation and inflammation The inflammation caused for viral, bacterial and parasitic infections, principally when untreated, might predispose the normal tissue to the malignant transformation (Macroviak, 1987). In colon cancer, ulcerative colitis and parasite Schistossoma japonicum are considered predisposing sources of chronic inflammation connected to cancer (Wiseman and Halliwell, 1996), while in oral cancer the candidiasis seems to be oncogenic (Lovas et al., 1989; Krogh, 1990). The ROS (reactive oxygen species)/ RNS (reactive nitrogen species) generation by inflammatory cells would are able to cause genetic damage and neoplastic transformation. The molecular basis of these effects is the formation of DNA strands breaks, sister chromatoid exchange and mutations, presumably caused by nuclear penetration of products resultant of phagocitose such as H2O2, which after converted in OH· (free radical) attack the DNA, damaged it in consequence of oxidative alteration in DNA bases (tymdine glycol, 5-hidroxymethyl-2'-deoxyuridine and 8-OhdG). This latter has also been identified in epidermis of nude mice exposed to near-UV. Inflammatory cells may also increase DNA damage in consequence of the activation of pro-carcinogens to DNA-damage species (aromatic amines, aflatoxins, strogens, phenols and polyciclic aromatic hydrocarbons) by ROS-dependent mechanism, as well as nitrosamines by RNS-dependent mechanism (Wiseman and Halliwell, 1996). Etiogenic Factors Anxiety Frequents stressful events have been reported preceding episodes of the symptoms in patients with erosive lichen planus, particularly in patients presenting depressive and hypochondriacal personality (Lowenthal and Pisanti, 1984; Berdghal J et al., 1995; Buckhardt et al., 1996). However, these results were not statistically confirmed in the study of Allen et al. (1986). None statistic difference was identified in the stress scores, when psycometric (MACL) test was used. In this same study, was not also verified any statistic correlation between the cortisol concentration and stress level (Rodstrom et al., 2001). Stress The stress may be caused by various stimuli (marriage, divorce, surgery, familiar dead, traumatism, judiciary process, grave disease and hospitalization), and requires an organic and/or emotional adaptation, which is characterized by energy spend superior than the normal state (Selye, 1946). For maintain the homeostasis, the hypothalamus stimuli to hypophysis to synthesize and to secrete ACTH (adrenocrticotrophic hormone), which induces the medullar and cortical suprarenal regions to rise the production of catecholamines and glycocorticoids, respectively, inhibiting the secretion of insulin, as well as increasing the secretion of glucagon and glycemia (Axelsson J, 1971; Gerich et al., 1976). In addition, studies have proofed that the stimulation prolonged with high doses of glycocorticoids produces an initial state of euphoria, which change to psicotic, paranoic and depressives states (Smith et al., 1973), such as occurs in some patients with lichen planus. Familial tendency The observation that some cases of lichen planus occur among the members of a same family suggests familial tendency. However, in spite of having been identified a greater grade of correlation between HLA antigens (HLA B7) and family members affected by lichen planus than in the normal population, or with the characteristics forms of lichen planus, the causes of this tendency stay still obscure (Coperman et al., 1978; Porter, Olsen and Barrett, 1997). These cases may be merely coincidental, considering that HLA antigens have been significantly increased in determined groups, such as occur in German patients with cutaneous LP (HLA-DR1), in Japanese patients (HLA-DRw9, HLA-DR3), in Chinese patients (HLA-DR9), in English patients (HLA-B27, HLA-B51, HLA-Bw57), in Israel Jewish patients (HLA-DR2), and in Sardinian patients (HLA-DR1); or perhaps to be related to a common, but unidentified environmental factor. Is possible that this common familial factor may be an viral agent, similarly at the increase of the frequency of HLA-DR6 allele, identified among Italian patients with hepatitis C virus-associate oral lichen planus (Carrozo et al., 2001). As the patients with oral lichen planus and also diabetic have greater frequency of HLA B5, B7, and BX antigens than non-diabetic patients with oral lichen planus, the identification of these and other antigens (HLA B15 and B18) may predispose a person to the development of lichen planus (Ognjenovic et al., 1998), principally if the patient is diabetic. Viruses The B hepatitis and C viruses have been implicated in the association of mucocutaneous lichen planus and chronic liver disease, mainly in Southern Europe and Japan. This association seems to occur, since some cases of skin lichenoid lesions develop themselves approximately three weeks after a hepatitis B vaccination (Pemberton et al., 2000). Some correlation has also been reported between lichen planus and other viruses (HGV, EBV, HPV), occasionally, resulting in malign transformation in the oral and genital mucosa (Vescovi et al., 2000). In the skin, this transformation seems to be infrequent, considering the existence of less than 30 cases of epidermoid carcinoma that developed themselves in cutaneous lichen planus lesions, and in only four cases with evolution to verrucous carcinoma (Castano et al., 1997). Allergy Pharmaceutical drugs, industrial compounds, dentistry material and inhaled particles have been implicated as some of the causatives agents. The ingestion of many other medicaments such as antimalarical, penicilamine, thiazide, diuretics, beta-blocker, nonsteroidal anti-inflammatory, quinidine and angiotensin-converting enzyme inhibitor have also been associated with the presence of lichen planus (Katta 2000). Recently, one case of lichenoid eruption drugs was reported with use of the non-steroidal anti-inflammatory drug salsalate used to treat arthritic paim (Powell et al., 2001). Gold, Mercuric choride, metallic mercury, amalgampower, thimerosal, phenylmercuric acetate, phenylmercuric acetate, nickel sulphate, potassium dicynoanurate, potassium dichromate, silver nitrate, stanic chloride katon CG metilmetacrylate were positive patch tests in 18 patients with oral lichenoid lesions and allergies to mercury compounds; while neomycin sulphate, nickel sulphate, fragrance mix, potassium dichromate, cobalt chloride, stannic chloride, methylmetacrylate, thiuram mix, wood tar mix were positive patch test in 3/15 patients with oral lichenoid lesions; but not in allergies to mercury compounds. In addition to presence of these components used in dentistry material (dental amalgam), the mercury compounds that are used also in vaccines, contact lens solutions, certain creams and contraceptives. Candida pseudohyphae identified in a high percentage of biopsies from lichenoid lesions has been connected with the exacerbation of these lesions, by mean of a reaction to infection or hypersensitization to allergens (Jones, Pinnel, Netti, 1991; Juhani et al., 1992). Solar Radiation The solar radiation may induce actinic lichen planus that clinically present itself as a brownish plaque with annular configuration, and less commonly, to show discrete and confluent papules and hyper-melanotic patches, sometimes assuming the appearance melasma-like. This lesion may present parakeratosis eczematous changes confined to the follicular epithelium, and a significant grade of solar elastosis has been also observed in these lesions (Salman et al., 1989). Besides, long-term exposure is carcinogenic, particularly, in persons presenting little pigmentation, because the actinic radiation induces to development of keratose, which is considered to be the more common pre-cancerous skin lesions (Kwa et al., 1992). Laser and solar radiation The treatment with the copper vapor laser (578 nm, yellow light, 15.9 and 31.8 J/cm2) seems not to accelerate the UV-induced photo-carcinogenesis, nor the laser exposure seems to have malignant potential itself, concluded Haerdersdal and Wulf (1996). However, at posterior work, the former author salient the importance of the pre and post-operative sun protection because the UV radiation increases the effects of the laser on the skin, since the pigmentation and scars increase of size as well as the epidermal thickness prolonging the wound healing in these areas (Haedersdal, 1999). Other data preoccupant, is the fact that, in the dependency of a defined wavelength light, the mitotic rate of normal and tumor cell may be affected for the laser by mean of a mechanism that involve the endogenous participation of porphirins and cytochromes, as primary receptors (Srokra et al., 1991). These results must be analyzed with caution, considering the crescent use of the modern lasers in the therapy of wrinkles, rhytides, actinically damage skin such as malign neoplasm (Hoenleutner et al., 1999), and on the oral cavity, particularly in the areas near to the lip, which is frequently under solar radiation, since 10 kJ per m2 (equivalent to 1 minimal erythema dose) of ultraviolet B and 150 kJ per m2 of ultraviolet A (0.2 minimal erythema dose) can induce 1% of micronuclei in fibroblasts, equivalent to induction due to 0.6 Gy of gamma radiation (Emri et al., 200). Immunopathogenesis Actually, there is an attempt of explicating the LP with basis in the development of a type IV hypersensitivity reaction, whose induction phase is connected with the interaction of endogenous or exogenous agent (allergen, drug, virus). This hypothesis has support in the immune-histochemistry identification of a great number of T lymphocytes, macrophages, as well as of a decreased number of B lymphocytes. Other cells, such as mast cell and Langerhans cells have also participation in the immune-pathogenesis of oral lichen planus, since these cells produce and/or express cytokines, adhesion molecules and growth factors, such as gamma interferon (CD8 lymphocytes, Langerhans cells), neuropeptides (mucosal nerves), MHC Class II keratinocytes), ELAM-1 (mast and endothelial cells), VCAM-1 (endothelial cells) TNF-a (mast cell), Histamine (mast and lymphocytes), IL-1 and IL-6 (damaged keratinocytes), IL-1, IL-3, IL-6, IL-8 (keratinocytes), and granulocytic-macrophage-colony stimulating factor (T lymphocytes), which are involved in the migration of lymphocytes to the basal membrane and epithelial regions, considering that these molecules promote the adhesion of these cells in components of the extra-cellular components, such as laminin, fibronectin, vitronectin, fibrinogen, trombospondin and Von willebrandt factor (Dockrell and Greespan, 1979; Walsh et al., 1990; Walsh et al., 1990;Eversole et al., 1994). Grinspan Syndrome The triad oral erosive lichen planus, mellitus diabetes and hypertension was describe by first time by Grinspan et al. in 1963 and confirmed by Grupper and Avul in 1965. In spite of 9 cases have been reported (www.ncbi.nlm.nih/entrez/query) until 2001, of what, one transformed itself in carcinoma (Colella, Itro, Corvo 1992), and three others were apparently drug-induced, when of the therapy for treating diabetes and hypertension (Lamey et al., 1990); 75 cases to discuss the connection between lichen planus and mellitus diabetes; and 29 cases to discuss the connection between lichen planus and hypertension; other studies have questioned the existence of Grinspan's syndrome. In them, was emphasized a not significant high frequency of patients with diabetes and high blood pressure, as well as any difference in glucose tolerance test between patient with lichen planus and the common people without lichen planus. Therefore, not supporting the hypothesis of the relationship lichen planus, glycemia and hypertension (Christensen et al., 1977; Silverman et al., 1985). Immediate biopsy or therapeutic trial of lichen planus A therapeutic trial with a drug regimen specific for vesicullobullous/vesiculoerosive lesions constitutes itself in a diagnostic procedure. If an oral autoimmune lesion does not respond to treatment a 2-week trial period, or if an isolated area is refractory to treatment, a biopsy must be ordered. If the lesions respond and clear with the time, the biopsy is unnecessary (Brown et al., 1992). This work has the propose of reporting one case clinically diagnosed as lichen planus at diabetic patient presenting hypertension and goiter, who developed benign (micro follicular thyroid adenoma) and malign neoplasm (skin epidermoid carcinoma), discussing the possible association among the variables presence of oral and cutaneous lichen planus, hypertension and mellitus diabetes, suggesting a possible mechanism in the attempt of explicating the association among these three variables.

Initital Manifestation of oral lichen planus (Bullous, erosive, reticular and plaque)

Report of the case                                      

PAL, feminine sex, 83-year-old, Italian decency, white, housewife, A blood group, not smoking, without alcoholic habit, using medication for treating diabetes (Glifage 1.7 mg/day - Merck, Rio de Janeiro) until 2000 and (Novolin N Penfil 100 UI/mL, 22 mg/day - Novo Nordisk do Brazil), in 2001; for treating hypertension (Verapamil 240mg/day - Basf, Rio de Janeiro; Glipizida 15 mg/day- Minidiab, Rio de Janeiro); osteoporosis (Ossopan 830 mg/day - Asta Médica, Rio de Janeiro), for treating goiter (Puran 100 mg/day); and for treating depression (Zoloft 25 mg/day - Pfeizer, São Paulo), complained itself of the presence of "balls" in the lip mucosa (cis). In this same time, reported "discomfort" in the thyroid glandule region, which increased with the suspension of the medication (L-thyroxine). Her medical history revealed that in 1992 there was realized a thyroid photoscan, whose result showed the presence of an increased glandule, with atypical form and nodule in the left lobe, receiving interpretation of goiter with nodule in the left lobe. In 1995 realized thyroid echography, which revealed right lobe (4.5 x 1.5 cm) with homogeneous texture and left lobe (8.5 x 6.7 x 6.5 cm) presenting heterogeneous texture and hyper calcifications areas of nodular and amorphous aspect. In 1997, was realized new thyroid echography in linear transdutor of high resolution (7.5 MHz), whose images showed the presence in the left lobe (9.9 x 5.7 x 3.6 cm - V= 95cc) of multi-nodular areas presenting colloid degeneration and amorphous calcifications nodules. The right lobe had 4.2 x 1.4 x 1.0 cm (V=8cc) and presented smooth borders, homogeneous texture and spissated isthmus. In 1995, during the anamnesis reported the presence of lesions in the inferior lip mucosa that started as vesicle painless, increased of size and afterward break acquiring the erosive aspect turning them painful. In addition, informed also that was under strong emotional stress (dead of her husband and familial judiciary process). After to have been realized an extra-oral physical examination, was observed the presence of leukoplastic lesions (not removable by the simple scrape) interlaced with erosive areas localized in the lip at intern mucosa, in whose median part was identified the presence of a big erosive area presenting inside vesicles and burns, initially transparent, but that with the growth, immediately before of breaking themselves, acquired yellowish color (fig 1). In the periphery region of this erosive area, was also observed the reticular aspect. The differential clinic diagnosis was of lichen planus or lichenoid reaction to drugs, and benign mucous membran pemphigoid. As the patient presented high blood glucose level, a biopsy of one incipient vesicle was not gone, until the glycemia to stay in normal level. However, when this occurred the lesions there were suffered remission, not being more indicated for the treatment the realization of the biopsy. In addition, as the patient was yet using medicament indicated to treat vesicle-bullous and vesicle-erosive lesions, and this conduct might be considered as one itself indicated diagnosis proceeding for a diabetic patient presenting high glucose level, the realization of biopsy, which might increase the risk/benefit rate, following the orientation of Brown et al. (1992), was discarded. After three years (1998), when of the collect of blood to examination of DNA necessary to conclusion of a familial judiciary process initiated in 1995, was observed the development of lesions that distributing themselves in the leg since the knee until the shin. These lesions started as short vesicles, bullae, which breaking themselves forming pruritic erosions and ulcerations areas. In 2000, developed depressive state, which intensified itself afterwards a thyroid surgery. In the second semester of this same year, was identified the presence of one lesion localized in the face, right side, lateral to the naris and nasolabial sulcus, which initially presented the aspect granular pruritic, acquiring the ulcerated aspect, being covered by squamas in its central portion. In this time, the patient consulted a medical that prescribed Berlison. In 2001, as the lesion did not regenerate, the patient consulted a dermatologist, who diagnosed as actinic keratose marking cryosurgery for July of 2001 (winter). At this time the patient presented more 9 actinic lesions. However, the patient did not submit herself to surgery. In November, when of a consult realized by the daughter's patient - without to exam the patient - was marked another date for the realization of cryosurgery (winter of 2002). In December, I suspected of malignance and required biopsy. The microscopic exam of a skin fragment (biopsy) with diameter of 0.2 cm x and 0.1 cm in profundity revealed the invasion of the derme presenting, dense mononuclear cellular and dilated pilous follicle infiltrated by dyskeratotic squamous cells, having origin in parakeratotic epiderm, whose diagnosis was squamous cell carcinoma, infiltrating superficial derma. In the day of receiving the diagnosis the patient developed recurrent oral lichen planus lesions. The dermal lesion surgically removed with free borders, presenting 2.0 x 1.1 x 0.9 cm and diameter of 0.4 cm, revealed the presence of an superficially invasive squamous cell carcinoma in collagen presenting elastosis, and developing itself in an atrophic epidermis (Laboratórios Reunidos, exam number 37003/01, Santa Maria, RS, Brazil). In this same year (2002), the patient developed sinusitis as well as suffered orthopedic surgery (february), and a laser application (July) in the right eye for treating cataract. In 2003, a dermal lesion localized in the left hemi-face received the diagnosis of keratosis seborrhea. Of particular in this lesion was the absence of accentuate mononuclear inflammatory infiltrate identified in region sub-epithelial in the lesion with the diagnosis of squamous cell carcinoma. In 2004, coinciding with the invasion of her rural propriety (stressing factor), again, presented lesions of LP with the same characteristic of the initial manifestation, however, less accentuated. As well cutaneuous lesions, particularly, in the regions of cutaneous fold that coincided with the change of the insulin that made use for the glargina insulin (Aventis Pharma, Deutschland) 25 I. U. , because until to correct the dose, the patient presented high glycemia, particularly, at night. In this time, the mean of glycemia was 234 mg/dl (Glucotrent, n. GA 02558095, UK) and 140 x 85 mmhg of arterial pressure (IQ System, SN 00_00132-012446, Japan). At this time, present the mean of the glycemia level around of 190 mg/dl (before of the dinner) for the dose of 32 I. U., with the mean of arterial pressure: 135 x 86 mmhg.

Manifestation of cutaneous lichen planus (ulceration, Wilckham's striae)

Material and Methods    

The results of the analysis laboratorial of the glucose level, at abrosia per 12 hours, were grouped according to the year, having been calculated the mean, standardized error, standardized derivation and variance (table 1). Was used student's test to compare the statistical differences in the glucose level per year, considering 1997 year as control, since in that year the patient had the glucose level next to normal, not presenting oral and cutaneous lichen planus lesion, as well as not reporting any event of high stress score (table 1). Indeed, was also evaluated the statistic difference (Student's test) between the glycemia level, anterior to the breakfast and sleep (table 2 and 3). The results of the laboratorial, at abrosia per 12 hours, and Glucotrent Plus Roche Method (before breakfast), realized in 2001 and 2002, were also submitted to Student's test (tables 1 and 2). The glucose level was statistically tested to the correlation between to presence or absence of stressing factors, as well as with the presence or not of lichen planus lesions, attributing the numerical valor 1 (absence of stress and lichen planus lesion) and 2 (presence of stress and lichen planus lesions). The presence or not of stress was established according to high scores obtained in KSP, PS and PFS tests, reported by Bergdhal et al. 1995. In addition, were also considered the presence or not of a particular one event, which normally is associated with high level of stress, such as divorce, surgery, familial dead, traumatism, judiciary process, grave disease and hospitalization. The possible association between the variables glucose level and systolic and diastolic pressures was evaluated in the next (January + April) and distant surgical time (May + Jun) by mean of linear correlation statistical test (table 4). The variables presenting a correlation coefficient < 0.500 were considered as presenting low statistic correlation, whereas what presenting correlation coefficient > 0.500, as presenting high statistical correlation. The correlation coefficient = 0.00 was considered without correlation between the two variables evaluated. The statistical tests were realized in Excel program, Microsoft.  

Details of cutaneous lichen planus lesions (reticular, bullous, papular, plaque)        

Results

The years of 1995 and 1996 (high glycemia) presented significant Student's test (p<0.01) with relation to 1997 year (controlled glycemia) (talbe 1). In 2001 and 2002, the difference between the glucose dosage laboratorial method (abrosia per 12 hours) and Glucotrent Plus Roche Method (before of breakfast) was not significant (p>0.05) (table 1 and 2). The glucose level before breakfast and of sleeping presented significant statistic difference (p<0.01) (table 2 and 3). The blood glucose level presented a low positive correlation (0.082) with the manifestation of lichen planus, as well as a high statistic correlation with the emotional and/or physical stress (0.601). The patient presented depression (dysthymia), high level of anxiety and characteristics of a high scores KSP and PFS, as well as intermediary score in PS. When the glucose level and blood pressure were tested before (January) and after (April + May + Jun) orthopedic surgery realized in February 2001, the statistic difference in the glucose level (p=0.363) was not significant (p>0.05), while the difference between the diastolic (p=0.003) and (p= 0.017) systolic pressure before and after surgery presented significant statistic difference (Student's test). In this period, the systolic pressure (0.002) and diastolic pressure (-0.05) showed low statistic correlation with to glycemia, in spite of having occurred in January (anterior to surgery) and in April (forty-five days after the surgery) a high statistical correlation between the glycemia and systolic pressure (0.9965) (0.6311), respectively; as well as a low statistic correlation to diastolic pressure (0.36) (0.15) in these two months. However, the statistical correlation between the variables glucose level and diastolic pressure was high (0.6925) in January, but low (0.157) in April, same having been not significant (p>0.05) the statistical difference between the systolic (0.105) and diastolic (0.322) pressures in this time (Student's test) (table 4).  

Recurrent oral lichen planus (erosive, reticular bullous, and Wilckham's striae)

Discussion 

In the case reported, the manifestation of lichen planus, diabetes and hypertension is according to the reports of Grinspan et al 1963, 1966 and Gruper and Avul 1965. However, the association of these variables has been questioned, since has not been identified among the patients with lichen planus a significant high frequency diabetes, or a glucose tolerance different of the normal population (Christensen et al., 1977; Silverman et al., 1985). These results were not confirmed in the present study, considering that, same using medication for controlling diabetes (Puran - until 2001 and Insulin- in 2001), the glucose average level was, in mean, superior to the normal level (85 -105 mg/dl). In addition, with Student's test was identified a significant statistic difference in the glucose level between the time of the first manifestation of lichen planus (1995) and the time in that the glucose level maintain next to the normal (1997), without to manifest lichen planus, or an major stressing factor (p<0.05). The test of statistic correlation between the glucose level and manifestation of lichen planus showed a low linear correlation coefficient (0.082) that indicates also the participation of other variables in the exacerbation of the lichen planus lesions. One of these other variables, responsible by the manifestation of lichen planus lesions, since was verified a high positive statistic correlation between the glycemia and stress (0.601), might be the physical and/or emotional stress of the patient between 1995 and 2002. The difference statistically significant (Student's test) in the systolic (p=0.017) and diastolic (p=0.003) pressures, before and after orthopedic surgery, suggested that the mean of the blood pressure was different in the pre and post surgery periods, indicating that the emotional and/or physical stress, connected to surgery, might be another variable responsible by the manifestation of Lichen Planus and elevation of the blood pressure, same being the patient using medication to low the blood pressure. Because was also verified, during this period, a low positive statistical correlation statistic between glycemia and systolic (0.097) and diastolic (0.066) pressures, is possible that not only the increase in the glucose level, in addition to the emotional and/or physical stress, is associated to hypertension, but also, considering this low positive correlation, which there is also the participation of other factors that might have contributed to modify the blood pressure. The association between glucose and blood pressure has support in the data of January (before surgery), when was identified a high positive correlation between glucose level and systolic pressure (0.9965) and diastolic (0.692) pressures, as well as in April (45 days after surgery), when was also verified a high positive correlation between glucose level and systolic (0.6311) pressure, but a low positive correlation between level of glucose and diastolic pressure (0.157). These results strongly suggest an association between emotional and/or physical stress and glycemia, as well as between glycemia and systolic and diastolic pressures, in spite of other variables to be also associated, principally, to latter. Possibly, the high statistic correlation between glycemia and systolic pressure might be explicated for an increase of the glucose level induced for the increased of the production of catecholamines and cortisol necessary to the production of the compensatory energy to the increase of the vascular tonus and of the contraction force of the myocardium, which is also induced by these hormones, when in the stress state. However, in spite of having occurred an significant statistic difference (Student's test) in the glucose level (p=0.01), systolic (p=0.035) and diastolic (p=0.035) between the time next (January + April) and distant surgical time (May + Jun), 75 days after the surgery (May), was verified a low negative correlation between glucose level and systolic (-0.26) and diastolic (-0.30) pressures, which might be associated to diminution or adaptation to the emotional and/or physical stress. Therefore, these results did not confirm the work of Allen et al. (1986), with relation to lack of association between lichen planus and stress or anxiety. In addition, the patient possessed all the characteristic of an high score KSP, PS and PFS reported by Bergdahl et al (1995), except with relation to "does not care about their health", but presented hipocondriasis. Besides, from 1997 to 2001, the patient constantly presented anxious state, developing accentuated depressive state in 2000, afterwards to thyroid surgery. In this same period, other situations connected to high score, such as the diabetes treatment, two neoplasms (micro follicular thyroid adenoma and skin epidermoid carcinoma), four surgeries, dead of spouse, and familial judiciary process, were reported by the patient as having accentuated her stress state. This apparent discrepancy of our study with relation to the study of Allen et al (1986) might be explicated by the fact of the sample used in the latter study to be constituted for patients non-diabetic, whose emotional and/or physical stress - in our vision - does not elevate the glycemia to a level able of exacerbating the lichen planus manifestation. Other data that supports this our inference was the not manifestation of lichen planus, when the glucose was in a level next to a normal valor (1997), as well as the fact of the first manifestation and of the recurrent lichen planus lesions to have only occurred when the glucose level was up to 130 mg/dL. Possibly, this association might not occur in patient non-diabetic. Is also possible that the increase of cortisol production in patient non diabetic - induced by stress - blockages the manifestation of lichen planus, because this hormone inhibits the synthesis of interferons and interleukines (IL-1a, IL-3, IL-6, IL-8) from lymphocytes and keratinocytes, suppressing the immune response mediated by these cells, as well as the synthesis of prostaglandins and leukotrienes, resultant of the inhibition of the formation of aracdonic acid, whose metabolism produce other mediators connected also to imunopathogenesis of the lichen planus. The significant statistical Student's test, at the level of glucose level between the year of the first manifestation of oral lichen planus (1995) and the year (1997), in that the patient presented glycemia near to normal, did not also confirmed the studies of Christensen et al. (1977) and Silverman Jr. (1985), but is according to the studies of Lündström (1983) and Smith (1977), which reported the possible association between lichen planus and diabetes (glucose level). The fact of some patients with lichen planus not to present diabetes or hypertension (the triad complete), such as reported by Christensen et al. (1977) and Silverman Jr. et al (1985), in our view, does not exclude the possibility of the Grinspan's syndrome, since might occur an situation similar to incomplete form of the Melkersson-Rosenthal syndrome, where are only present one of the symptoms or signal of the classic triad, connected to less frequents manifestations. Therefore, in all patient presenting lichen planus and diabetes; lichen planus and hypertention; or lichen planus and stress must be considered the possibility of developing the Grinspan's syndrome, as well as if the patient only presenting lichen planus of being an undisclosed diabetic, such as reported by Smith (1977). Because there is not cure to lichen planus, the treatment is palliative and must objective to reduce the pain during the alimentation, as well as the pruritus that is present in the dermal lesions, promoting greater comfort to the patient. For this, is indicated to use topic or systemic corticoids, anti-histaminic, fungicide drugs and topic and systemic retinoids. In the grave cases is also indicated the association of systemic corticoids and imunesupressive drugs. At the case for us reported was prescribed topic corticoid, fungicide and antibiotic, causing the remission of the skin lesions and diminution of the pruritus. All patients presenting oral lichen planus must be evaluated and accomplished with attention about the possibility of developing epidermoid carcinoma, not only in the oral cavity, but also in any other region that possess epithelial tissue, such as occurred in the present study, and in the case reported by Colella, Itro, Corvo (1992). The clinical characteristics of the dermal lesions - presence of bullae, papules, erosions and ulcerations - as well as the fact of the patient to present oral lichen planus and to develop skin epidermoid carcinoma (fig 4) suggested the diagnostic of ulcerative lichen planus. The oral lesions presented the characteristic of bullous, erosive and reticular lichen planus . Therefore, confirming the potential of malignance attributed the lichen planus lesions. In spite of the epithelial borders of the ulcer at that developed itself the carcinoma to present itself atrophic with degeneration of basal cells, and to show discontinuous basal membrane, presenting separation between the epithelium and connective tissue, as well as to present mononuclear cellular infiltrate suggestive of lichen planus, this lesion presented also areas of elastosis compatible with actinic keratose. Other possible origin to epidermoid carcinoma might be one previous lesion of actinic lichen planus, since this lesion might have started in the youth. Besides, was also identified, in addition to exposition of actinic radiation and traumatic (irritation chronic); the skin pigmentation (direct Italian descendent) favorable to development of SCC; as well as the existence possible genetic predisposing, considering the familial history of neoplasia (recurrent pleomorphic adenoma/adenocarcinoma), Down's syndrome and the presence of lichen planus, diseases that have been also connected with genetic alterations. As the skin SCC was diagnosed in initial stage connected to actinic radiation; to have < 1 cm of diameter and < 2mm in depth; to be restrict to superficial derma (grade 2), without to presented invasion perineural; and to show accentuate lympho-plasmocytic infiltration, predominantly mononuclear (grade 1), corn pearl (grade 1), moderate Keratinization individual of cells (grade 2), moderate nuclear and cellular polimorphism (grade 2), moderate number of giants cell (grade 2), low mitotic activity (grade 1), areas with diffuse pattern of invasion (grade 4), invasion vascular by individual cell, but absence of embolization (grade 3), Histological score: 2,1, Histologic grade: III; this patient possess great possibilities of not developing metastasis, if its possible immune response - that was accentuate - to kill the infiltrating vascular neoplastic cells. The fact of the lesion diagnosed in 2003 as seborreic keratosis (left hemi-face) not to be present this cellular infiltrate, suggest that the mononuclear infiltrate sub-epithelial present in the squamous cell carcinoma (smaller lesion in the right hemi-face) was an response immune from our patient to antigens expressed in the neoplastic cells, which in this case may have prevent to dissemination of metastases. With relation to the risk of developing a second primary skin squammous cell carcinoma, considering the number of solar keratose identified and her expectance of life, is around of (5%). In summary, the glucose level presented significant difference statistic (Student's test) in the time of the first manifestation of lichen planus (1995) and in the absence of these lesions and glycemia near to normal (1997) (p<0.01), suggesting that the rise in the glucose level is associated with the first manifestation and exacerbation of lichen planus lesions. The low positive correlation between the association of the glucose level and manifestation of lichen planus (0.082), systolic (0.033) and diastolic (0.127) pressures suggest that other variables may be involved. One of these variables, at least in part, may be attributed to the emotional and/or physical stress, considering to high positive correlation between glycemia and emotional and/or physical stress (0.601), whose mechanism may be connected to elevation of glycemia, consequent to the increase of the production of cathecolamines and cortisol induced by the emotional and/or physical stress. Therefore, association of the elevation of the glucose level, blood pressure and lichen planus lesions is according to report of Grinspan in 1963, 1965 and of Gruper in 1966, as well as confirm the association between lichen planus and diabetes reported by Smith 1977 and Lüdström et al., 1985. REFERENCE Berdghal J, Otsman PO, Anneroth G, Perris H et al. (1995) Psychological aspects with oral lichenoid reactions. Acta Odontol Scand 53: 236-241. Brown RS, Bottomley W, Abramowitich K, Langlais R (1992) Immediate biopsy versus a therapeutic trial in the diagnosis and treatment of vesiculobullous/vesiculoerosive oral lesions. Oral Surg Oral Med Oral Pathol 73: 694-697. Burkhardt NH, Burker EJ, Burkes EJ, Wolf L (1996) Assessing of the characteristics of patients with oral lichen planus. J Am Dent Ass 127: 648, 651-652, 655-656. Carrozo M, Francia Di Celle P, Gandolfo S, Carbone M et al. (2001) Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus. Br J Dermatol 144: 803-808. Castano E, Lopez-Rios F, Alvarez-Fernandes JG, Rodrigues-Peralto JL et al (1997). Verrucous carcinoma in association with hypertrophic lichen planus. Clin Exp Derm 22: 23-25. Christensen E, Holmstrup P, Wiberg-Jorgensen F, Neumann-Jensen B et al. (1977) Arterial blood pressure in patients with lichen planus. J Oral Pathol 6: 139-142. Coperman PW, Tan RS, Timlin D, Samman PD (1978) Familial lichen planus. Another disease or a distinct people? Br J dermatol 98: 573-577. Dockrell HM, Greepan JS (1979) Histochemical identification of T cells in the lichen planus. Oral Surg 48: 42, 1979. Emri G, Wenczl E, Van Erp P, Jans J, Roza L, Horkay I, Schothorst AA. Low doses of UVB or UVA induce chromosomal aberrations in cultured human skin cells. J Invest Dermatol 2000 Sep;115(3):435-40. Eversole LR et al (1994) Immunopathology of oral mucosal ulcerative, descamative, and bullous lesions. Selective revision of literature. Oral Surg Oral Med Oral Pathol 77: 555-571 Girodi SC, Pape HD, Krueger GR (1995) p53 and PCNA expression in carciongenesis of the oropharyngeal mucosa. Eur J Cancer Oral Oncol 31B: 403-404. Grinspan D, Diaz J, Villapol LO et al (1966) Lichen rubber planis de la muquese buccale son association a un diabete. Bull Soc Fr Dermatol Syphiligr 72, 721, 1966. Haedersdal M (199) Cutaneous side effects from laser treatment of the skin: skin cancer, scars, wounds, pigmentary changes, and purpura-use of pulsed dye laser, cooper vapor laser, and argon laser. Acta Derm Venereol Suppl 207: 1-32. Haedersdal M, Wulf HC (1996) Cooper vapor laser and photocarcinogenesis in hairless mice. Lasers Surg Med 18: 331-396. Katta R (2000) Lichen planus. Am Fam Physician 62: 1786. Kin J, Yook JL, Lee EH, Ryu MH et al. (2001) Evaluation of the premalignant potential in the lichen planus using interphase cytogenetics. J Oral Med 30: 65-72. Krog P (1990) The role of yeasts in oral cancer by means of endogenous nitrosation. Acta Odontol Scand 48: 85-88. Laine J, Kalino K, Forssell H, Happonen RP (1992) Resolution of oral lichenoid lesions after replacement of amalgam restorations in patients allergic to mercury compounds. Br J Dermatol 126: 10-15. Lamey PG, Gibson J, Barclay SC, Miller S (1990) Grinspan's syndrome: drug-induced phenomenon? Oral Surg Oral Med Oral Pathol 70: 184-185.Lovas JG, Harsany BB, El Geneidy AK (1989) Oral lichenoid dysplasia. A clinic pathologic analysis. Oral Surg Oral Med Oral Pathol 68: 57-63. Lüdström IMC Incidence of diabetes in patients with lichen planus. Int J Oral Surg 12: 147-152. Macrowiak PA (1987) Microbial oncogenesis. Am J Med 82: 79-97. Martinez-Lara I, Gonzales-Moles MA, Ruiz-Avila I, Bravo M et al. (1996) Proliferating cell nuclear antigen (PCNA) as a marker of dysplasia in oral mucosa. Acta Stomatol Belg 93: 29-32 Mignogna MD, Lo Muzzio LL, Lo Ruzzo LL, Fedele S et al. (2001) Clinical guidelines in the early detection of oral squamous cell carcinoma arising in the oral lichen planus: a 5-years experience. Oral oncol 37: 262-267. Ognjenovic M, Kareolovic L, Mikelic M, Tadin I et al. (1998) Oral lichen planus and HLA B Coll Antropol 22 (suppl): 93-96. Pemberton MN, Sloan P, Takker NS (2000) Oral lichenoid lesions after hepatitis B vaccination. Oral Surg Oral Med Oral Pathol Oral Radiol Endotod 89: 717-719. Porter SR, Kirby A, Olsen I (1997) Immunologic aspect of dermal and oral lichen planus. Oral Surg Oral Med Oral Pathol 83: 358-366. Salman SM, Kibbi AG, Zaynoun S (1989) Actinic lichen planus. A clinicpathologic study of 16 patients. J Am Acad Dermatol 20: 226-231. Selye H (1946) The general adaptation syndrome and the diseases of adaptation. J Clin endocrin Metabol 6: 117-196. Silverman SJR, Gorsky M, Lozada-Nur FA (1985) The prospective follow-up study of 570 patients with lichen planus: persistence, remission, and association. Oral Surg 60: 30-34. Smith GP (1973) Adrenal hormones and emotional behavior. Prog Physiol Psychol 5: 299. Smith MJA (1977) Oral lichen planus and mellitus diabetes: a possible association. J Oral Med 32:110-112, 1977. Sroka R, Schaffer M, Fuchs C, Pongrats T et al (1999) Effects on the mitosis of normal and tumor cells induced by light treatment of different wavelengths. Lasers Surg Med 25: 263-271. Valente G, Pagamo M, Carrozzo M, Carbone M et al. (2001) Sequential immunoexpression of p53 expression in biopsies of oral lichen planus undergoing malignant evolution. J Oral Pathol 30: 135-140. Rodstrom PO, Jontell M, Hakberg M, Bergremm U et al. (2001) Erosive lichen planus and cortisol salivary. J Oral Pathol 30: 253-260. Walsh LJ, Savage NW, Ishii T, Seymur GJ (1990) Immunohistologic analysis of epithelial cell populations in oral lichen planus. J Oral Pathol Med 19: 177-181. Walsh LJ, Savage NW, Ishii T, Seymur GJ (1990) Immunopathogenesis of oral lichen planus. J Oral Pathol Med 19: 389-396. Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313: 17-29. Younes F, Quartey EL, Kiguwa S, Patridge M (1996) Expression of TNF and 55-kDa in epidermis, oral mucosa, lichen planus, leukoplakia and squamous cell carcinoma. Oral Dis 2: 25-31.   

Actinic Keratose (greater) and epidermoid carcinoma (smaller), details 

References 

Berdghal J, Otsman PO, Anneroth G, Perris H et al. (1995) Psychological aspects with oral lichenoid reactions. Acta Odontol Scand 53: 236-241. Brown RS, Bottomley W, Abramowitich K, Langlais R (1992) Immediate biopsy versus a therapeutic trial in the diagnosis and treatment of vesiculobullous/vesiculoerosive oral lesions. Oral Surg Oral Med Oral Pathol 73: 694-697. Burkhardt NH, Burker EJ, Burkes EJ, Wolf L (1996) Assessing of the characteristics of patients with oral lichen planus. J Am Dent Ass 127: 648, 651-652, 655-656. Carrozo M, Francia Di Celle P, Gandolfo S, Carbone M et al. (2001) Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus. Br J Dermatol 144: 803-808. Castano E, Lopez-Rios F, Alvarez-Fernandes JG, Rodrigues-Peralto JL et al (1997). Verrucous carcinoma in association with hypertrophic lichen planus. Clin Exp Derm 22: 23-25. Christensen E, Holmstrup P, Wiberg-Jorgensen F, Neumann-Jensen B et al. (1977) Arterial blood pressure in patients with lichen planus. J Oral Pathol 6: 139-142. Coperman PW, Tan RS, Timlin D, Samman PD (1978) Familial lichen planus. Another disease or a distinct people? Br J dermatol 98: 573-577. Dockrell HM, Greepan JS (1979) Histochemical identification of T cells in the lichen planus. Oral Surg 48: 42, 1979. Emri G, Wenczl E, Van Erp P, Jans J, Roza L, Horkay I, Schothorst AA. Low doses of UVB or UVA induce chromosomal aberrations in cultured human skin cells. J Invest Dermatol 2000 Sep;115(3):435-40. Eversole LR et al (1994) Immunopathology of oral mucosal ulcerative, descamative, and bullous lesions. Selective revision of literature. Oral Surg Oral Med Oral Pathol 77: 555-571 Girodi SC, Pape HD, Krueger GR (1995) p53 and PCNA expression in carciongenesis of the oropharyngeal mucosa. Eur J Cancer Oral Oncol 31B: 403-404. Grinspan D, Diaz J, Villapol LO et al (1966) Lichen rubber planis de la muquese buccale son association a un diabete. Bull Soc Fr Dermatol Syphiligr 72, 721, 1966. Haedersdal M (199) Cutaneous side effects from laser treatment of the skin: skin cancer, scars, wounds, pigmentary changes, and purpura-use of pulsed dye laser, cooper vapor laser, and argon laser. Acta Derm Venereol Suppl 207: 1-32. Haedersdal M, Wulf HC (1996) Cooper vapor laser and photocarcinogenesis in hairless mice. Lasers Surg Med 18: 331-396. Katta R (2000) Lichen planus. Am Fam Physician 62: 1786. Kin J, Yook JL, Lee EH, Ryu MH et al. (2001) Evaluation of the premalignant potential in the lichen planus using interphase cytogenetics. J Oral Med 30: 65-72. Krog P (1990) The role of yeasts in oral cancer by means of endogenous nitrosation. Acta Odontol Scand 48: 85-88. Laine J, Kalino K, Forssell H, Happonen RP (1992) Resolution of oral lichenoid lesions after replacement of amalgam restorations in patients allergic to mercury compounds. Br J Dermatol 126: 10-15. Lamey PG, Gibson J, Barclay SC, Miller S (1990) Grinspan's syndrome: drug-induced phenomenon? Oral Surg Oral Med Oral Pathol 70: 184-185.Lovas JG, Harsany BB, El Geneidy AK (1989) Oral lichenoid dysplasia. A clinic pathologic analysis. Oral Surg Oral Med Oral Pathol 68: 57-63. Lüdström IMC Incidence of diabetes in patients with lichen planus. Int J Oral Surg 12: 147-152. Macrowiak PA (1987) Microbial oncogenesis. Am J Med 82: 79-97. Martinez-Lara I, Gonzales-Moles MA, Ruiz-Avila I, Bravo M et al. (1996) Proliferating cell nuclear antigen (PCNA) as a marker of dysplasia in oral mucosa. Acta Stomatol Belg 93: 29-32 Mignogna MD, Lo Muzzio LL, Lo Ruzzo LL, Fedele S et al. (2001) Clinical guidelines in the early detection of oral squamous cell carcinoma arising in the oral lichen planus: a 5-years experience. Oral oncol 37: 262-267. Ognjenovic M, Kareolovic L, Mikelic M, Tadin I et al. (1998) Oral lichen planus and HLA B Coll Antropol 22 (suppl): 93-96. Pemberton MN, Sloan P, Takker NS (2000) Oral lichenoid lesions after hepatitis B vaccination. Oral Surg Oral Med Oral Pathol Oral Radiol Endotod 89: 717-719. Porter SR, Kirby A, Olsen I (1997) Immunologic aspect of dermal and oral lichen planus. Oral Surg Oral Med Oral Pathol 83: 358-366. Salman SM, Kibbi AG, Zaynoun S (1989) Actinic lichen planus. A clinicpathologic study of 16 patients. J Am Acad Dermatol 20: 226-231. Selye H (1946) The general adaptation syndrome and the diseases of adaptation. J Clin endocrin Metabol 6: 117-196. Silverman SJR, Gorsky M, Lozada-Nur FA (1985) The prospective follow-up study of 570 patients with lichen planus: persistence, remission, and association. Oral Surg 60: 30-34. Smith GP (1973) Adrenal hormones and emotional behavior. Prog Physiol Psychol 5: 299. Smith MJA (1977) Oral lichen planus and mellitus diabetes: a possible association. J Oral Med 32:110-112, 1977. Sroka R, Schaffer M, Fuchs C, Pongrats T et al (1999) Effects on the mitosis of normal and tumor cells induced by light treatment of different wavelengths. Lasers Surg Med 25: 263-271. Valente G, Pagamo M, Carrozzo M, Carbone M et al. (2001) Sequential immunoexpression of p53 expression in biopsies of oral lichen planus undergoing malignant evolution. J Oral Pathol 30: 135-140. Rodstrom PO, Jontell M, Hakberg M, Bergremm U et al. (2001) Erosive lichen planus and cortisol salivary. J Oral Pathol 30: 253-260. Walsh LJ, Savage NW, Ishii T, Seymur GJ (1990) Immunohistologic analysis of epithelial cell populations in oral lichen planus. J Oral Pathol Med 19: 177-181. Walsh LJ, Savage NW, Ishii T, Seymur GJ (1990) Immunopathogenesis of oral lichen planus. J Oral Pathol Med 19: 389-396. Wiseman H, Halliwell B (1996) Damage to DNA by reactive oxygen and nitrogen species: role in inflammatory disease and progression to cancer. Biochem J 313: 17-29. Younes F, Quartey EL, Kiguwa S, Patridge M (1996) Expression of TNF and 55-kDa in epidermis, oral mucosa, lichen planus, leukoplakia and squamous cell carcinoma. Oral Dis 2: 25-31.